Thesis (PhD)--Montana State University--Bozeman, 2009. / Typescript. Chairperson, Graduate Committee: Brent M. Peyton. Includes bibliographical references.

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In the United States, over 90 contaminants in community water supplies (CWS) are regulated based on maximum contaminant limits (MCLs) set by the Environmental Protection Agency under the Safe Drinking Water Act. These limits are crucial to the health of over 90% of the US population who rely on CWS for their drinking water. Despite advancements in safer water, questions remain about the potential role of prolonged exposures to contaminants at sub-regulatory levels in chronic diseases. Historically, conducting epidemiologic studies of drinking water exposures in the United States has been challenging due to the fragmented availability of CWS service areas and contaminant information, which varies depending on each state’s efforts. This dissertation attempts to overcome some of these barriers by collaborating with long-standing institutes in California to evaluate the relationship between drinking water contaminants (arsenic, uranium, and trihalomethanes) and the risks of cardiovascular disease (CVD) and chronic kidney disease (CKD) in a large prospective cohort. The California Teachers Study (CTS) cohort is comprised of over 130,000 women living across the state and followed for health outcomes, including CVD and CKD, since enrollment (1995-1996). The California Office of Environmental Health Hazard and Assessment (OEHHA) houses some of the most detailed information about CWS available in the United States. With their partnership, we consolidated three decades (1990-2020) worth of yearly contaminant data from CWS. Thanks to a statewide effort that gathered service boundary data from local agencies, we were able to identify CWS serving participants’ residential addresses. Ultimately, these efforts produced new drinking water exposure data available in the CTS cohort, accessible for the analyses of associated health outcomes. Chapter 1 provides an overview of the novel contributions and methods of this dissertation, and background knowledge about the three common drinking water contaminants under study—arsenic, uranium, and trihalomethanes. The three epidemiologic studies included in this dissertation were designed to evaluate the relationship between these contaminants and health outcomes, selected based on previous toxicologic evidence. To this end, we detail current knowledge on the relationships between a) arsenic and CVD, b) uranium and arsenic and CKD, and c) trihalomethanes and CKD. Chapter 2 details our efforts to construct residential histories of CTS participants using address data collected throughout follow-up (1995-2018). Environmental epidemiologic studies using geospatial data often estimate exposure at a participant’s residence upon enrollment, but mobility during the exposure period can lead to misclassification. We aimed to mitigate this issue using address records that have been self-reported and collected from the US Postal Service, LexisNexis, Experian, and California Cancer Registry. We identified records of the same address based on geo-coordinate distance (≤250m) and street name similarity. We consolidated addresses, prioritizing those confirmed by participants during follow-up questionnaires, and estimating the duration lived at each address using dates associated with records (e.g., date-first-seen). During 23-years of follow-up, about half of participants moved (48%, including 14% out-of-state). We observed greater mobility among younger women, Hispanic or Latina women, and those in metropolitan and lower socioeconomic status areas. The cumulative proportion of in-state movers remaining eligible for analysis was 21%, 32%, and 41% at 5-, 10-, and 20-years post-enrollment, respectively. Using self-reported information collected 10 years after enrollment, we correctly identified 94% of self-identified movers and 95% of non-movers as having moved or not moved from their enrollment address. This dataset provides a foundation for estimating long-term exposure to drinking water contaminants evaluated in this dissertation, and supports other epidemiologic studies of diverse environmental exposures and health outcomes in this cohort. Chapter 3 details our first epidemiologic analysis evaluating the relationship between long-term arsenic exposure from CWS and CVD risk in the CTS cohort. Inorganic arsenic in drinking water is linked to atherosclerosis and cardiovascular disease. However, risk is uncertain at lower levels present in CWS, currently regulated at the federal maximum contaminant level of 10µg/L. Using statewide healthcare administrative records from enrollment through follow-up (1995-2018), we identified fatal and nonfatal cases of ischemic heart disease (IHD) and CVD (including stroke). Participants’ residential addresses were linked to a network of CWS boundaries and annual arsenic concentrations (1990-2020). Most participants resided in areas served by a CWS (92%). Exposure was calculated as a time-varying, 10-year moving average up to a participant’s event, death, or end of follow-up. Using multivariable-adjusted Cox models, we estimated hazard ratios (HRs) and 95% confidence intervals (95%CIs) for the risk of IHD or CVD. We evaluated arsenic exposure categorized by concentration thresholds relevant to regulation standards (<1.00, 1.00-2.99, 3.00-4.99, 5.00-9.99, ≥10µg/L) and continuously using a log2-transformation (i.e., per doubling). We also stratified analyses by age, body mass index (BMI), and smoking status. This analysis included 98,250 participants, 6,119 IHD cases and 9,936 CVD cases. The HRs for IHD at concentration thresholds (ref:<1µg/L) were 1.06 (95%CI=1.00-1.12) at 1.00-2.99µg/L, 1.05 (95%CI=0.94-1.17) at 3.00-4.99µg/L, 1.20 (95%CI=1.02-1.41) at 5.00-9.99µg/L, and 1.42 (95%CI=1.10-1.84) at ≥10µg/L. HRs for every doubling of wAs exposure were 1.04 (95%CI=1.02-1.06) for IHD and 1.02 (95%CI=1.01-1.04) for CVD. We observed statistically stronger risk among those ≤55 versus >55 years at enrollment (pinteraction=0.006 and 0.012 for IHD and CVD, respectively). This study demonstrates that long-term arsenic exposure from CWS, at and below the regulatory limit, may increase cardiovascular disease risk, particularly IHD. Chapter 4 details our second epidemiologic analysis evaluating uranium and arsenic from CWS and CKD risk in the CTS cohort. Metals/metalloids in drinking water, including uranium and arsenic, have been linked to adverse kidney effects and may contribute to CKD risk, but few epidemiologic studies exist. Annual average concentrations of uranium and arsenic were obtained for CWS serving participants’ residential address(es). We calculated participant’s average exposure from enrollment in 1995 to 2005. CKD cases were ascertained from inpatient hospitalization records beginning in 2005, once diagnostic coding was adopted, through 2018. Our analysis included 6,185 moderate to end stage CKD cases among 88,185 women. We evaluated exposure categorized by concentration thresholds relevant to regulatory standards, up to ½ the current regulatory limit (uranium=15µg/L; arsenic=5µg/L), and continuously on the log scale per interquartile range (IQR). We used mixed-effect multivariable-adjusted Cox models to estimate HRs and 95%CIs of CKD by uranium or arsenic levels. We also conducted analyses stratified by risk factors and comorbidities. Exposures at the 50th (25th, 75th) percentiles were 3.1 (0.9, 5.6) µg/L for uranium, and 1.0 (0.6, 1.8) µg/L for arsenic. Higher uranium exposure, relative to <2µg/L, was associated with CKD risk, with HRs of 1.20 (95%CI=1.07-1.35) at 2.0-<5.0µg/L, 1.08 (95%CI=0.95-1.22) at 5.0-<10µg/L, 1.33 (95%CI=1.15, 1.54) at 10-<15µg/L, and 1.32 (95%CI=1.09-1.58) at ≥15µg/L (ptrend=0.024). We found no overall association between arsenic and CKD (log IQR; HR=1.02, 95%CI=0.98-1.07). However, risk from arsenic was statistically different by age and comorbidity status, with risk only observed among younger individuals (≤55 years), and those who developed cardiovascular disease or diabetes. Uranium exposure from drinking water below the current regulatory limit may increase CKD risk. Relatively low, chronic exposure to arsenic may affect kidney function among those with comorbidities. Chapter 5 details our third and final epidemiologic analysis evaluating trihalomethanes in residential CWS and CKD risk in the CTS cohort. Disinfection byproducts from water chlorination, including trihalomethanes (THMs), have been associated with bladder cancer and adverse birth outcomes. Despite mechanistic evidence of nephrotoxic effects, especially brominated THMs, no epidemiologic studies to date have evaluated CKD risk. This study included 89,158 women with 6,232 moderate to end stage CKD cases identified from statewide healthcare administrative records (2005-2018). Average concentrations of four THMs, including three brominated THMs, were calculated for CWS serving participants’ residential addresses from 1995-2005. We estimated HRs and 95%CIs using mixed-effect multivariable-adjusted Cox models. A g-computation mixture analysis approach was used to estimate the overall effect and relative contribution of brominated THMs, chloroform (non-brominated THM), as well as uranium and arsenic—other potentially nephrotoxic metals in CWS previously evaluated. Median (25th, 75th, 95th percentiles) were 5.5 (0.5, 24.1, 57.8) µg/L for total THMs and 2.7 (0.6, 11.3, 30.0) µg/L for brominated THMs. In flexible exposure-response models, we observed a positive relationship between total THMs and CKD risk, which was stronger for brominated THMs. The HRs (95%CIs) of CKD risk from brominated THMs at the highest two exposure categories (75th-94th, ≥95th, versus <25th) were 1.23 (1.13-1.33) and 1.43 (1.23-1.66), respectively; ptrend<0.001. Brominated THMs were the largest contributor (53%) to the overall mixture effect on CKD risk, followed by uranium (35%), arsenic (6%), and chloroform (5%). Trihalomethanes in water, in particular brominated trihalomethanes which are not regulated separately, may contribute to CKD development, even at levels below the current US regulatory limit (80µg/L). Chapter 6 concludes this dissertation by summarizing our findings, highlighting the policy implications, relevance to other populations, and discussing future directions. Recently, the US EPA has released a geospatial dataset of CWS boundaries across the country that can be used in conjunction with national contaminant data. This development underscores the growing recognition for more research on drinking water quality and health. We hope that the methods developed and used in our analyses will be informative to future studies, and that there will be opportunities for replication of our findings to better inform policy and protect the health of populations nationwide.